Ontario Institute for Cancer Research, Department of Informatics and Bio-computing Program, Toronto, Canada.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.
Toxicol Appl Pharmacol. 2014 Feb 1;274(3):445-54. doi: 10.1016/j.taap.2013.12.004. Epub 2013 Dec 16.
Despite several decades of research, the complete mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other xenobiotic agonists of the aryl hydrocarbon receptor (AHR) cause toxicity remains unclear. While it has been shown that the AHR is required for all major manifestations of toxicity, the specific downstream changes involved in the development of toxic phenotypes remain unknown. Here we examine a panel of 13 genes that are AHR-regulated in many species and tissues. We profiled their hepatic mRNA abundances in two rat strains with very different sensitivities to TCDD: the TCDD-sensitive Long-Evans (Turku/AB; L-E) and the TCDD-resistant Han/Wistar (Kuopio; H/W). We evaluated doses ranging from 0 to 3000μg/kg at 19h after TCDD exposure and time points ranging from 1.5 to 384h after exposure to 100μg/kg TCDD. Twelve of 13 genes responded to TCDD in at least one strain, and seven of these showed statistically significant inter-strain differences in the time course analysis (Aldh3a1, Cyp1a2, Cyp1b1, Cyp2a1, Fmo1, Nfe2l2 and Nqo1). Cyp2s1 did not respond to TCDD in either rat strain. Five genes exhibited biphasic responses to TCDD insult (Ahrr, Aldh3a1, Cyp1b1, Nfe2l2 and Nqo1), suggesting a secondary event, such as association with additional transcriptional modulators. Of the 12 genes that responded to TCDD during the dose-response analysis, none had an ED50 equivalent to that of Cyp1a1, the most sensitive gene in this study, while nine genes responded to doses at least 10-100 fold higher, in at least one strain (Ahrr (L-E), Aldh3a1 (both), Cyp1a2 (both), Cyp1b1 (both), Cyp2a1 (L-E), Inmt (both), Nfe2l2 (L-E), Nqo1 (L-E) and Tiparp (both)). These data shed new light on the association of the AHR target genes with TCDD toxicity, and in particular the seven genes exhibiting strain-specific differences represent strong candidate mediators of Type-II toxicities.
尽管已经进行了几十年的研究，但 2,3,7,8-四氯二苯并对二恶英（TCDD）和其他芳基烃受体（AHR）的外源性激动剂引起毒性的确切机制仍不清楚。虽然已经表明 AHR 是所有毒性主要表现所必需的，但在有毒表型发展过程中涉及的特定下游变化仍然未知。在这里，我们研究了一组在许多物种和组织中受 AHR 调节的 13 个基因。我们在两种对 TCDD 非常敏感的大鼠品系中对其肝脏 mRNA 丰度进行了分析：TCDD 敏感的长耳（Turku/AB；L-E）和 TCDD 抗性的汉/维斯特拉（Kuopio；H/W）。我们评估了从 0 到 3000μg/kg 的剂量，在 TCDD 暴露后 19 小时，并在暴露于 100μg/kg TCDD 后的 1.5 至 384 小时的时间点。13 个基因中有 12 个在至少一种品系中对 TCDD 有反应，其中 7 个在时间过程分析中表现出统计学上显著的品系差异（Aldh3a1、Cyp1a2、Cyp1b1、Cyp2a1、Fmo1、Nfe2l2 和 Nqo1）。Cyp2s1 在两种大鼠品系中均未对 TCDD 作出反应。五个基因对 TCDD 损伤表现出双相反应（Ahrr、Aldh3a1、Cyp1b1、Nfe2l2 和 Nqo1），这表明存在继发性事件，例如与其他转录调节剂的关联。在剂量反应分析中对 TCDD 有反应的 12 个基因中，没有一个的 ED50 相当于本研究中最敏感的基因 Cyp1a1，而至少有 9 个基因在至少一种品系中对至少 10-100 倍更高的剂量有反应（Ahrr（L-E）、Aldh3a1（两者）、Cyp1a2（两者）、Cyp1b1（两者）、Cyp2a1（L-E）、Inmt（两者）、Nfe2l2（L-E）、Nqo1（L-E）和 Tiparp（两者））。这些数据为 AHR 靶基因与 TCDD 毒性之间的关联提供了新的线索，特别是在两种品系中都表现出差异的七个基因是 II 型毒性的强有力候选介质。
